Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis. Current treatments for AIDS (Dagani, Chem. Eng. News, Nov. 23, 1987 pp. 41-49) involve administration of compounds such 2',3'-dideoxycytidine, trisodium phosphonoformate, ammonium 21-tungsto-9-antimoniate, 1-b-D-ribofuranoxyl-1,2,4-triazole-3-carboxamide, 3'-azido-3'-deoxythymidine, and adriamycin that inhibit viral DNA synthesis; compounds such as AL-721 and polymannoacetate which may prevent HIV from penetrating the host cell; and compounds which treat the opportunistic infections caused by the immunosupression resulting from HIV infection. None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity and bone marrow cytopenia.
Proteases are enzymes which cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I. Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce high blood pressure in vivo. However, no therapeutically useful renin protease inhibitors have been developed, due to problems of oral availability and in vivo stability.
The genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gag gene products. See Wellink, Arch. Virol. 98 1 (1988). Retroviral proteases most commonly process the gag precursor into the core proteins, and also process the pol precursor into reverse transcriptase and retroviral protease.
The correct processing of the precursor polyproteins by the retroviral protease is necessary for the assembly of the infectious virions. It has been shown that in vitro mutagenesis that produces protease-defective virus leads to the production of immature core forms which lack infectivity. See Crawford, J. Virol. 53, 899 (1985); Katoh et al., Virology 145 280 (1985). Therefore, retroviral protease inhibition provides an attractive possible target for antiviral therapy. See Mitsuya, Nature 325 775 (1987).
Moore, Biochem. Biophys. Res. Commun., 159 420 (1989) discloses peptidyl inhibitors of HIV protease. Erickson, European Patent Application No. WO 89/10752, discloses derivatives of peptides which are inhibitors of HIV protease. Kemf, European Patent Application No. 90109319.5, discloses derivatives of peptides which are inhibitors of HIV protease. Also Handa, European Patent Application No. 89110717.9 discloses aminoacid derivatives as inhibitors of HIV protease. Jadhav, U.S. patent application Ser. No. 07/531,971, filed Jun. 1, 1990 (now abandoned), discloses inhibitors of HIV protease.
EP 402 646 discloses retroviral protease inhibiting compounds of the formula: A-X-B where A and B are independently substituted amino, functionalized alkyl, functionalized acyl, functionalized heterocyclic or functionalized (heterocyclic)alkyl and X is a linking group.
The ability to inhibit a viral protease provides a method for blocking viral replication and therefore a treatment for diseases, and AIDS in particular, that may have fewer side effects and be more efficacious when compared to current treatments. The topic of this patent application is substituted dihydroxypropylamine containing peptide derivatives, which compounds are capable of inhibiting viral protease and which compounds serve as a means of combating viral diseases such as AIDS. The substituted dihydroxypropylamine containing peptide derivatives of this invention provide significant improvements over protease inhibitors that are known in the art. A large number of compounds have been reported to be renin inhibitors, but have suffered from lack of adequate bio-availability and are thus not useful as therapeutic agents. This poor activity has been ascribed to the unusually high molecular weight of renin inhibitors, to inadequate solubility properties, and to the presence of a number of peptide bonds, which are vulnerable to cleavage by mammalian proteases. Retroviral proteases, HIV protease in particular, is capable of cleaving phenylalanine-proline or tyrosine-proline peptide bonds. However, phenylalanine-proline or tyrosine-proline peptide bonds are not susceptible to cleavage by mammalian proteases. The dihydroxypropylamine containing derivatives described herein have a distinct advantage in this regard, in that many of them are derivatives of dipeptide isosteres of phenylalanine-proline or tyrosine-proline. This feature makes them highly specific inhibitors HIV protease. The compounds of this invention do not inhibit enzymes such as renin or pepsin; nor are they cleaved by chymotrypsin. The structure-activity requirements of HIV protease inhibitors differ from those of renin inhibitors suggesting that HIV protease inhibitors may not be inhibitors of human renin.
Other HIV protease inhibitors have been reported, but to date very few have shown activity against viral replication in human cells. This lack of cellular activity is probably due in part to the factors discussed above for renin inhibitors. Unlike other HIV protease inhibitors, the dihydroxypropylamine containing peptide derivatives disclosed herein show potent inhibition of viral replication in human cells. The compounds of this invention, in addition to basic nitrogens, contain a highly hydrophilic diol unit which imparts favorable physical properties such as solubility in common organic and aqueous media. These physical characteristics are important in improving the bioavailability of HIV protease inhibitors.
Another aspect of the present invention is a process for the preparation of 1,2-diols. The 1,2-diol unit is one of the most ubiquitous funtional groups in nature, and consequently a wealth of methods leading to its synthesis have been developed. Foremost in this arsenal are the catalytic osmylation of olefins (Wai et al., J. Am. Chem. Soc. 1989, 111, 1123), ring opening of epoxides (Behrens and Sharpless, J. Org. Chem., 1985, 50, 5696), reduction or alkylation of a-hydroxy/alkoxy carbonyls (Davis et al., J. Org. Chem., 1989, 54, 2021). Common to all of these approaches is the preexistence of the central carbon-carbon bond of the diol function. Methods that lead directly to a 1,2-diol via formation of this bond are less common and include the reaction of an a- alkoxy anion (Cohen and Lin, J. Am. Chem. Soc., 1984, 106, 1130), with a carbonyl and the reductive coupling of two carbonyls (ie., pinacol coupling). Pons and Santelli, Tetrahedron, 1988, 44, 4295.
Of all these methods, pinacol coupling is conceptually one of the simplest methods for the synthesis of 1,2-diols. Consequently, a number of methods have been developed which utilize this reaction for the preparation of these compounds. For example, McMurry et al. report the preparation of a 1,2-diol by pinacol coupling of a dialdehyde in the presence of TiCl.sub.3 (dimethoxyethane).sub.2 /Zn-Cu in dimethoxyethane. McMurray et al., Tetrahedron Lett., 1989, 30, 1173. In a recent review article, Pons and Santelli describe many other methods leading to 1,2-diols which rely on low valent titanium complexes. Pons and Santelli, Tetrahedron, 1988, 44, 4295. Freudenberger et al. disclose a method which utilizes a vanadium (II) complex, [V.sub.2 Cl.sub.3 (THF).sub.6 ].sub.2 [Zn.sub.2 Cl.sub.6 ] to couple aldehydes. Freudenberger et al., J. Am. Chem. Soc., 1989, 111, 8014. Finally an improved method for the preparation of 1,2-diols which utilizes the catalyst of Freudenberger et al. has been disclosed. Jadhav, see U.S. Pat. No. 5,294,720.
While these methods are generally useful for the preparation of 1,2-diols, only Jadhav, U.S. patent application Ser. No. 07/531,971, filed Jun. 1, 1990 teaches how amino moieties can be incorporated into the diols. There is a need for other processes capable of providing such diols. It is an object of the present invention to provide such a process. In addition, the process of the present invention is capable of providing stereochemically pure diols containing at least three contiguous chiral centers. In these respects, the current invention is an improvement over the prior art.